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Structure-Activity Relationship Study of Cannabidiol-Based Analogs as Negative Allosteric Modulators of the μ-Opioid Receptor. | LitMetric

Structure-Activity Relationship Study of Cannabidiol-Based Analogs as Negative Allosteric Modulators of the μ-Opioid Receptor.

J Med Chem

Gill Center for Biomolecular Science, Department of Psychological and Brain Sciences, Program in Neuroscience, Indiana University, Bloomington, Indiana 47405, United States.

Published: July 2023

AI Article Synopsis

Article Abstract

The US faces an unprecedented surge in fatal drug overdoses. Naloxone, the only antidote for opiate overdose, competes at the mu opioid receptor (μOR) orthosteric site. Naloxone struggles against fentanyl-class synthetic opioids that now cause ∼80% of deaths. Negative allosteric modulators (NAMs) targeting secondary sites may noncompetitively downregulate μOR activation. (-)-Cannabidiol ((-)-CBD) is a candidate μOR NAM. To explore its therapeutic potential, we evaluated the structure-activity relationships among CBD analogs to identify NAMs with increased potency. Using a cyclic AMP assay, we characterize reversal of μOR activation by 15 CBD analogs, several of which proved more potent than (-)-CBD. Comparative docking investigations suggest that potent compounds interact with a putative allosteric pocket to stabilize the inactive μOR conformation. Finally, these compounds enhance naloxone displacement of fentanyl from the orthosteric site. Our results suggest that CBD analogs offer considerable potential for the development of next-generation antidotes for opioid overdose.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11299522PMC
http://dx.doi.org/10.1021/acs.jmedchem.3c00061DOI Listing

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